Natural killer cell-derived granzyme B as a therapeutic target for alleviating graft injury during liver transplantation.
10.1016/j.apsb.2025.07.042
- Author:
Kai WANG
1
;
Zhoucheng WANG
2
;
Xin SHAO
3
;
Lijun MENG
4
;
Chuanjun LIU
5
;
Nasha QIU
4
;
Wenwen GE
2
;
Yutong CHEN
6
;
Xiao TANG
2
;
Xiaodong WANG
6
;
Zhengxing LIAN
4
;
Ruhong ZHOU
7
;
Shusen ZHENG
8
;
Xiaohui FAN
3
;
Xiao XU
1
Author Information
1. General Surgery, Cancer Center, Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou 310024, China.
2. Department of Surgery, Zhejiang University School of Medicine, Hangzhou 310058, China.
3. Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
4. Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou 310006, China.
5. College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.
6. The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou 310053, China.
7. Institute of Quantitative Biology, Shanghai Institute for Advanced Study, College of Life Sciences, Zhejiang University, Hangzhou 310027, China.
8. Shulan Hospital Affiliated to Zhejiang Shuren University, Shulan International Medical College, Hangzhou 310015, China.
- Publication Type:Journal Article
- Keywords:
Adoptive immunotherapy;
Granzyme B;
Hepatic ischemia-reperfusion injury;
Liver transplantation;
Molecular dynamics;
Nanomedicine;
Natural killer cells;
Translational medicine
- From:
Acta Pharmaceutica Sinica B
2025;15(10):5277-5293
- CountryChina
- Language:English
-
Abstract:
Liver transplantation (LT) has become a standard treatment for end-stage liver diseases, and graft injury is intricately associated with poor prognosis. Granzyme B (GZMB) plays a vital role in natural killer (NK) cell biology, but whether NK-derived GZMB affects graft injury remains elusive. Through the analysis of single-cell RNA-sequencing data obtained from human LT grafts and the isolation of lymphocytes from mouse livers following ischemia-reperfusion injury (IRI), we demonstrated that 2NK cells with high expression of GZMB are enriched in patients and mice. Both systemically and liver-targeted depletion of NK cells led to a notable reduction in GZMB+ cell infiltration, subsequently resulting in diminished graft injury. Notably, the reconstitution of Il2rg -/- Rag2 -/- mice with purified Gzmb-KO NK cells demonstrated superior outcomes compared to those with wild-type NK cells. Crucially, global knockout of GZMB and pharmacological inhibition exhibited remarkable improvements in liver function in both mouse IRI and rat LT models. Moreover, a phosphorylated derivative of FDA-approved vidarabine was identified as an effective inhibitor of mouse GZMB activity by molecular dynamics, which could provide a potential avenue for therapeutic intervention. Therefore, targeting NK cell-derived GZMB during the LT process suggests potential therapeutic strategies to improve post-transplant outcomes.
